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1. |
Ras biochemistry and farnesyl transferase inhibitors: a literature survey |
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Anti-Cancer Drugs,
Volume 12,
Issue 3,
2001,
Page 163-184
M Crul,
G de Klerk,
J Beijnen,
J Schellens,
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摘要:
ver the last decades, knowledge on the genetic defects involved in tumor formation and growth has increased rapidly. This has launched the development of novel anticancer agents, interfering with the proteins encoded by the identified mutated genes. One gene of particular interest isras, which is found mutated at high frequency in a number of malignancies. The Ras protein is involved in signal transduction: it passes on stimuli from extracellular factors to the cell nucleus, thereby changing the expression of a number of growth regulating genes. Mutated Ras proteins remain longer in their active form than normal Ras proteins, resulting in an overstimulation of the proliferative pathway. In order to function, Ras proteins must undergo a series of post-translational modifications, the most important of which is farnesylation. Inhibition of Ras can be accomplished through inhibition of farnesyl transferase, the enzyme responsible for this modification. With this aim, a number of agents, designated farnesyl transferase inhibitors (FTIs), have been developed that possess antineoplastic activity. Several of them have recently entered clinical trials. Even though clinical testing is still at an early stage, antitumor activity has been observed. At the same time, knowledge on the biochemical mechanisms through which these drugs exert their activity is expanding. Apart from Ras, they also target other cellular proteins that require farnesylation to become activated, e.g. RhoB. Inhibition of the farnesylation of RhoB results in growth blockade of the exposed tumor cells as well as an increase in the rate of apoptosis. In conclusion, FTIs present a promising class of anticancer agents, acting through biochemical modulation of the tumor cells.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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2. |
Granulocyte colony stimulating factors: How different are they? How to make a decision? |
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Anti-Cancer Drugs,
Volume 12,
Issue 3,
2001,
Page 185-191
Françoise Martin-Christin,
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摘要:
Two granulocyte colony stimulating factors (G-CSFs) are available for clinical use in Europe: filgrastim (Neupogen®) and lenograstim (Granocyte®). The purpose of this literature review is to study how they differ, the clinical implications of these differences (especially in terms of efficacy) and the economic impact of these differences. From a chemical point of view the two molecules are not identical. Their amino acid sequence is different and one is glycosylated, whereas the other is not. The important question to ask is what these structural differences mean for the patient. It appears that glycosylation has important consequences in terms of efficacy. Several recent comparative studies, bothin vitroandin vivo, in animals and in humans, reinforce this idea which was often shared intuitively by physicians. In economical terms, in hospitals where the exact dosages are used (150 μg/m2or 19.2 million units (MU)/m2for Granocyte, and 5 μg/kg or 0.5 MU/kg for Neupogen), the choice of G-CSF must be made according to the daily cost of treatment which, for an average patient, means comparing the price of 325 μg of Neupogen and of 255 μg of Granocyte. This is in fact equal to comparing the price per MU of each product. In hospitals where one vial per patient per day is used whatever be their weight or body surface area, the price per MU and the price per vial should be considered together, puting into perspective the potential therapeutic benefit for patients, one vial of Granocyte 34 containing more MU than one vial of Neupogen 30.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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3. |
Phase I and pharmacokinetic study of the orally administered farnesyl transferase inhibitor R115777 in patients with advanced solid tumors |
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Anti-Cancer Drugs,
Volume 12,
Issue 3,
2001,
Page 193-197
C Punt,
L van Maanen,
C Bol,
W Seifert,
D Wagener,
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摘要:
R115777 is a novel selective inhibitor of farnesyl transferase, an enzyme that is involved in the proliferation of the malignant cell type. This study was designed to determine the toxicity, maximal tolerated dose and pharmacokinetics of R115777 when given orally b.i.d. for 28 days followed by 1-2 weeks of rest. Patients with advanced solid tumors for whom no standard therapy was available could enter the study. The starting dose of R115777 was 200 mg/dose and inter- as well as intra-patient dose escalations were performed with increments of 100 mg/dose. Nine patients entered the study and received in total 23 treatment cycles. A dose of 300 mg b.i.d. proved feasible with grade 4 neutropenia occurring in one of six patients who completed the first treatment cycle. Other toxicities were infrequent. Pharmacokinetic analysis demonstrated that peak plasma concentrations of 881±393 ng/ml were reached within 1-5 h. No accumulation of R115777 was observed over a 28-day period. The study was terminated based on these results together with the observation from a related phase I study in which higher doses of R115777 were associated with the frequent occurrence of grade 3-4 myelosuppression. We conclude that the recommended dose of R115777 given for 28 days followed by 1-2 weeks of rest is 300 mg b.i.d. Myelosuppression is the dose-limiting toxicity.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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4. |
Selection of candidates for oral etoposide salvage chemotherapy in heavily pretreated breast cancer patients |
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Anti-Cancer Drugs,
Volume 12,
Issue 3,
2001,
Page 199-204
Monika Jagodic,
Tanja Cufer,
Branko Zakotnik,
Jozica Cervek,
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摘要:
Metastatic breast cancer (MBC) is still in most cases an uncurable disease and the main goal of treatment is a good quality of life for these patients. Therefore it is very important to select patients who are appropriate candidates for the particular salvage chemotherapy (CT) schedule. The aim of our study was to assess treatment response to oral etoposide, and to analyze its relationship with patients' and disease characteristics. Seventy-five patients with bidimensionally measurable MBC were included into our study. For most of the patients treatment with etoposide was third-line CT regimen and most of them (90%) had been exposed to previous anthracycline-based CT. Etoposide was administered orally at a dose of 100 mg/day for 10 days every 3 weeks. The overall response rate was 37% (95% CI: 27-50%) with a median time to progression (TTP) and survival of 4.5 and 12 months, respectively. Patients with a long disease-free interval, predominant soft tissue and bone metastases, and less than three metastatic sites responded better to oral etoposide; however, a significantly better response was achieved only in those who had responded to previous CT (46 versus 19%,p= 0.04), especially to anthracyclines (50 versus 17%,p= 0.016). Response to previous anthracycline-based regimen was the only characteristic that significantly influenced TTP (median TTP: 7 versus 2.5 months,p= 0.0066) and survival (median survival: 13.8 versus 5 months,p= 0.0072). Toxic side effects were generally mild. Salvage CT with oral etoposide is an appropriate treatment for patients who respond to previous CT, particularly to anthracyclines. It combines a favorable toxicity profile with the major advantage of an oral drug administered at home.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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5. |
Ifosfamide and mitoxantrone in the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck |
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Anti-Cancer Drugs,
Volume 12,
Issue 3,
2001,
Page 205-208
Dietmar Thurnher,
Johannes Kornfehl,
Martin Burian,
Claudia Gedlicka,
Edgar Selzer,
Christian Quint,
Csilla Neuchrist,
Gabriela Kornek,
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摘要:
A phase II study was performed to assess the safety and efficacy of ifosfamide and mitoxantrone in recurrent and/or metastatic squamous cell carcinomas of the head and neck. Treatment consisted of ifosfamide 1500 mg/m2in 1000 ml saline, infused over 60 min and mesna 20% of the total dose of ifosfamide in three doses for 3 days combined with mitoxantrone 12 mg/m2given as a short infusion on day 1. Treatment courses were repeated every 4 weeks until a total of six cycles. Twenty-two patients entered this trial, 13 of whom had received chemo- and radiation therapy, and nine patients who underwent radiation therapy with or without prior surgery. We observed no objective response, with the exception of two patients who experienced minor response (reduction of tumor size of 25%). The dose-limiting toxicity was myelosuppression with grade 3/4 leukocytopenia in seven patients (32%) and grade 3/4 neutropenia in 15 (68%). Severe organ toxicity except alopecia (91%) was not observed. Ifosfamide combined with mitoxantrone does not improve the therapeutic armentarium in recurrent squamous cell carcinoma of the head and neck.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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6. |
Unexpected severe myelotoxicity of gemcitabine in pretreated breast cancer patients |
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Anti-Cancer Drugs,
Volume 12,
Issue 3,
2001,
Page 209-212
Gottfried Locker,
Catharina Wenzel,
Manuela Schmidinger,
Michael Gnant,
Christine Marosi,
Raimund Jakesz,
Christoph Zielinski,
Guenther Steger,
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摘要:
Gemcitabine is a chemotherapeutic agent with proven antitumor effects in pancreatic and non-small cell lung cancer; however, studies establishing the definite significance in other solid tumors are stiII in progress. We herein present three female patients with advanced breast cancer who received gemcitabine as salvage chemotherapy. Gemcitabine at a dose of 1250 mg/m2was scheduled for days 1, 8 and 15 with a subsequent rest for 1 week. However, within 1 week after the very first administration of gemcitabine myelotoxicity WHO grade IV occurred in all patients, leading to discontinuation of therapy. In two patients this gemcitabine-induced hematotoxicity could be overcome by means of vigorous supportive care, but one patient died after cerebral bleeding due to severe thrombocytopenia. We conclude that gemcitabine in heavily pretreated breast cancer patients should only be used with extreme caution with special focus on platelet counts until solid data from clinical studies for doses and schedules are available.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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7. |
Preclinical antitumor activity of the azonafide series of anthracene-based DNA intercalators |
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Anti-Cancer Drugs,
Volume 12,
Issue 3,
2001,
Page 213-220
Robert Dorr,
James Liddil,
Salah Sami,
William Remers,
Evan Hersh,
David Alberts,
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摘要:
The azonafides are a series of anthracene-based DNA intercalators which inhibit tumor cell growthin vitroat low nanomolar concentrations and are not affected by the multidrug resistance phenomenon (MDR). Prior studies have described antitumor efficacy in murine tumor models including L-1210 and P-388 leukemias, and B-16 melanoma. The current results extend these cell line observations to human tumors tested in the NCI panel of 56 cell lines, in freshly isolated tumors tested in colony-forming assays in soft agar and in several animal models. In the NCI panel, the overall mean 50% cell kill (LC50) for the unsubstituted azonafide, AMP-1, was 10−5.53M, with some selectivity noted in melanomas (10−6.22M). The mean LC50for the 6-ethoxy substituted analog, AMP-53, was 10−5.53M, with some selectivity found in non-small cell lung cancer (10−5.91) and renal cell carcinoma (10−5.84). In freshly isolated human tumors tested in soft agar, there was marked activity (mean IC50in μg/ml) for AMP-53 in four cell types: breast cancer (0.09), lung cancer (0.06), renal cell carcinomas (0.06) and multiple myeloma (0.03). These effects were superior to doxorubicin and to several other azonafides, including AMP-1, AMP-104 and the 6-hydroxyethoxy derivative, AMP-115. Compound AMP-1 was shown to be superior to amonafide in the mammary 16C breast cancer model in B6CF31 mice, but it had little activity in Colon-38 nor in M5076 ovarian sarcomasin vivo. Nine azonafides were evaluated in the Lewis lung cancer model in C57/bl mice, but only AMP-53 demonstrated significant efficacy with a treated/control×100% (T/C) value of 30%. Because AMP-53 demonstrated the greatest breadth of activity, it was then evaluated in several human tumor cell lines growing in mice with severe combined immunodeficiency disease (SCID). Only three tumors were sensitive (T/C<42%), including HL-60 leukemia (T/C=39%), MCF-7 breast cancer (T/C=39%) and A549 non-small cell lung cancer (T/C=37%). Overall, these results demonstrate that the 6-ethoxy substituted azonafide, AMP-53, has consistent (in vitroandin vivo) experimental antitumor activity in human breast and lung cancer, and could be considered for clinical testing in patients with MDR tumors.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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8. |
Antitumor activity, optimum administration method and pharmacokinetics of 13,14-dihydro-15-deoxy-δ7-prostaglandin A1methyl ester (TEI-9826) integrated in lipid microspheres (Lipo TEI-9826) |
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Anti-Cancer Drugs,
Volume 12,
Issue 3,
2001,
Page 221-234
Shoji Fukushima,
Yoshikazu Takeuchi,
Shuichi Kishimoto,
Shoichi Yamashita,
Kenji Uetsuki,
Satoshi Shirakawa,
Masaaki Suzuki,
Kyoji Furuta,
Ryoji Noyori,
Hiroshi Sasaki,
Yoshihiro Kikuchi,
Tsunekazu Kita,
Takao Yamori,
Junichi Sawada,
Michio Kojima,
Atsuo Hazato,
Seiji Kurozumi,
Masanori Fukushima,
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摘要:
13,14-Dihydro-15-deoxy-δ7-prostaglandin A1methyl ester (TEI-9826), an antitumor prostaglandin analog, is a candidate for clinical trial. In the present study, we examined its biological stabilityin vitro, antitumor activityin vitroandin vivo, and pharmacokinetics. Although TEI-9826 was rapidly hydrolyzed to the carboxylic acid form (TOK-4528), TOK-4528 as well as δ12-prostaglandin J2(PGJ2) were found to be stable in rat, mouse and human serumin vitro. TEI-9826 exhibited nearly identical or greater potential antitumor activity compared to δ12-PGJ2and δ7-PGA1in vitroagainst Colon26 tumor cells. Further evaluation of TEI-9826 using the 38 human cancer cell lines panel and COMPARE analysis suggested that its mode of action is quite different from other anticancer agents that are currently used. TEI-9826 was integrated into lipid microspheres (Lipo TEI-9826) for dosing. Growth inhibition by Lipo TEI-9826 against Colon26 tumor inoculated s.c. in mice depended on administration route, i.e. at 80 mg/kg, no growth suppressive effect was observed for daily bolus i.v., but significant growth suppressive effect was observed for daily i.p., daily s.c. every other day s.c. and 4 times a day continuous (5 min) i.v. These tumor growth-suppressive effects were cytostatic and the tumor started to regrow at the end or a few days after the end of administration. The pharmacokinetic study suggested that maintaining the blood level of TEI-9826 and/or TOK-4528 was essential for their antitumor effects. These results show that continuous i.v. infusion might be the most suitable administration method of Lipo TEI-9826 for clinical trial.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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9. |
Biodistribution of NX211, liposomal lurtotecan, in tumor-bearing mice |
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Anti-Cancer Drugs,
Volume 12,
Issue 3,
2001,
Page 235-245
John Desjardins,
Elizabeth Abbott,
David Emerson,
Blake Tomkinson,
Jeremy Leray,
Eric Brown,
Marta Hamilton,
Larry Dihel,
Mieke Ptaszynski,
Raymond Bendele,
Frank Richardson,
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摘要:
Prolonging tumor exposure to topoisomerase I inhibitors has been correlated to enhance the efficacy of those agents. Lurtotecan, a water-soluble camptothecin analog, was formulated as a liposomal drug, NX211, to enhance the delivery of drug to tumors. Tumor-bearing mice were treated with either [14C]NX211 containing [14C]lurtotecan, [3H]NX211 containing [3H]phosphatidylcholine or [14C]lurtotecan, euthanized at selected times post-injection, and tissues, plasma, urine and feces were collected. These studies demonstrated that KB tumors of [14C]NX211-treated mice had approximately 70-fold greater concentrations of [14C]lurtotecan at 24 h, respectively, compared to concentrations of [14C]lurtotecan of the KB tumors of [14C]lurtotecan-treated mice. The area under curve (AUC) from 0 to 48 h of [14C]lurtotecan for the KB tumors of [14C]NX211-treated animals was over 17-fold greater than the AUC of [14C]lurtotecan for the tumors of [14C]lurtotecan-treated animals. Treatment with [3H]NX211 demonstrated that the lipid component continually accumulated over 24 h in the tissues. HPLC analysis of extracted material from tumors of [14C]NX211-treated mice showed that more than 95% of the radioactive material was intact [14C]lurtotecan. These findings are one of the keys justifying the development of a liposomal formulation of lurtotecan, which has the intent to increase tumor exposure and increase antitumor efficacy.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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10. |
Sequential gene expression of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and lung resistance protein: functional activity of P-gp and MRP present in the doxorubicin-resistant human K562 cell lines |
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Anti-Cancer Drugs,
Volume 12,
Issue 3,
2001,
Page 247-258
Fabienne Grandjean,
Laure Brémaud,
Mireille Verdier,
Jacques Robert,
Marie-Hélène Ratinaud,
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摘要:
Previous studies have reported that P-glycoprotein (P-gp), a transmembrane efflux pump involved in multidrug resistance (MDR), was overexpressed in the doxorubicin (Dox)-resistant human erythroleukemia cell line K562. Nevertheless, several results suggested that P-gp was not the only mechanism involved in these resistant cells. Sequential co-expression of other MDR-associated proteins was sometimes reported, as MDR-associated protein (MRP) and lung resistance protein (LRP), in different MDR cell lines. Thus, mRNA expression and stability of P-gp, MRP and LRP were analyzed, while their corresponding protein levels were quantified in correlation with functional assay, in the K562 cell line and two Dox-resistant variants (K562/R). Their P-gp content was in accordance with their degree of resistance, but not as much in the level of mRNA expression, suggesting a post-transcriptional regulation. On the other hand, MRP could play a minor role in MDR because of an unchanged expression in K562/R sublines. A surprising progressive disappearance of LRP in both resistant cells suggested that the original mechanism of drug redistribution may be operative, involving a negative role for LRP.
ISSN:0959-4973
出版商:OVID
年代:2001
数据来源: OVID
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